chr3-38566465-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_001099404.2(SCN5A):c.3784G>A(p.Gly1262Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1262C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.3784G>A | p.Gly1262Ser | missense_variant | 21/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.3781G>A | p.Gly1261Ser | missense_variant | 21/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.3784G>A | p.Gly1262Ser | missense_variant | 21/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.3781G>A | p.Gly1261Ser | missense_variant | 21/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251464Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135906
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461728Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727152
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74342
ClinVar
Submissions by phenotype
Brugada syndrome 1 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2004 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Feb 21, 2020 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 27, 2019 | Reported in individuals with DCM and HCM (Priganc et al., 2016), an individual referred for Brugada syndrome testing (Kapplinger et al., 2010), and a child with noncompaction cardiomyopathy (van Waning et al., 2018); Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID#9399; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32048431, 31677787, 24903439, 19336922, 22581653, 18436145, 19027780, 15338453, 27554632, 29447731, 30662450, 20129283, 24136861, 31019283, 30193851, 31737537, 32533946, 33131149) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2023 | Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) indicates that this missense variant is expected to disrupt SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1262 of the SCN5A protein (p.Gly1262Ser). This variant is present in population databases (rs137854616, gnomAD 0.01%). This missense change has been observed in individual(s) with Brugada syndrome and/or dilated cardiomyopathy or hypertrophic cardiomyopathy and Brugada syndrome (PMID: 15338453, 20129283, 27554632, 30193851). ClinVar contains an entry for this variant (Variation ID: 9399). - |
Long QT syndrome 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Ventricular fibrillation, paroxysmal familial, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
SCN5A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The SCN5A c.3784G>A (p.Gly1262Ser) missense variant has been reported in two studies in which it is found in a total of seven individuals in a heterozygous state, including in one proband with Brugada syndrome, the proband's affected brother and as yet two unaffected children, in one additional unrelated individual with Brugada syndrome, in one individual diagnosed with dilated cardiomyopathy, and in one individual diagnosed with hypertrophic cardiomyopathy (Shin et al. 2004; Priganc et al. 2016). The p.Gly1262Ser variant was absent from 352 control chromosomes, but is reported at a frequency of 0.00013 in the South Asian population of the Genome Aggregation Database. Based on the evidence, the p.Gly1262Ser variant is classified as a variant of uncertain significance but suspicious for pathogenicity for SCN5A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Sick sinus syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Progressive familial heart block, type 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 07, 2022 | The c.3784G>A (p.G1262S) alteration is located in exon 21 (coding exon 20) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 3784, causing the glycine (G) at amino acid position 1262 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 04, 2023 | This missense variant replaces glycine with serine at codon 1262 of the SCN5A protein. This variant is also known as c.3781G>A (p.Gly1261Ser) based on a different transcript NM_000335.5. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with Brugada syndrome including two who were from the same family (PMID: 15338453, 20129283), two individuals affected with dilated cardiomyopathy and one individual with hypertrophic cardiomyopathy (PMID: 27554632), and in another individual affected with noncompaction cardiomyopathy and atrial fibrillation (Van Waning 2020, dissertation, Erasmus University Rotterdam). This variant has been identified in 8/282850 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Brugada syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Brugada syndrome in the following publications (PMID:15338453;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at